The Janus kinase (Jak) family is composed of four phosphotransferases, Jak1, Jak2, Jak3 and Tyrosine kinase 2 (Tyk2), each of which associates with a distinct set of cytokine receptors, mediating a cascade of autophosphorylation and subsequent activation of Signal Transducer and Activation of Transcription (STAT) proteins. Activated STATs dissociate from the cytokine receptor and translocate to the cell nucleus to regulate transcription of selected STAT-dependent pro-inflammatory genes. Disruption or dysregulation of the Jak-STAT pathways, such as through genetic mutations or increased localized concentrations of inflammatory cytokines, is a key driver of various pathologies.
Significant evidence exists for the role of inflammatory cytokines, interleukin (IL)-12 and IL- 23, in inflammatory and autoimmune diseases. IL-23 shares a p40 subunit with IL-12 but each has a unique p19 subunit. It has been demonstrated that mice deficient in either p40, p19, IL-12, or IL-23 are protected from disease in models of inflammatory bowel disease (IBD) and psoriasis. See, e.g., Hue et al., J. Exp. Med. (2006) 203:2473-2483 (IBD); Hong et al., J. Immunol. (1999) 162:7480-7491 (psoriasis). Dysregulated expression of IL-12 and/or IL-23 has been found in patients suffering from psoriasis and inflammatory bowel disease. See, e.g., Lee et al., J. Exp. Med. (2004) 199:125-130 (psoriasis); Piskin et al., J. Immunol. (2006) 176:1908-1915 (psoriasis); Piskin et al., Ex. Dermatol. (2004) 13:764-772 (psoriasis); Duffin et al., Dermatol. Ther. (2010) 23:101-113 (psoriasis); Abraham and Cho, Annu. Rev. Med. (2009) 60:97-110 (IBD); and Yen et al., J. Clin. Invest. (2006) 116:1310-1316 (IBD). The anti IL- 12/23 p40 monoclonal antibody, ustekinumab (Stelara®), has been found efficacious in the treatment of psoriasis and Crohn's disease (CD). See, e.g., Mortezavi et al.,Curr. Treat. Options in Rheum. (2015) 1:197-209 (psoriasis); Settesoldi et al., Expert Rev. Gastroenterol. Hepatol. (2014) 8:5-13 (CD); Rashid F., Lichtenstein G.R. “New Non-anti-TNF-α Biological Therapies for the Treatment of Inflammatory Bowel Disease.” Pediatric Inflammatory Bowel Disease. Ed. Mamula P., Grossman A., Baldassano R., Kelsen J., Markowitz J.; Cham: Springer International Publishing AG, 2017. pp 425-450 (CD). Risankisumab, an anti-IL-23 p19 monoclonal antibody, has also been found efficacious in the treatment of psoriasis and Crohn's disease. See, e.g., Papp et al., N. Engl. J. Med. (2017) 376:1551-1560 (psoriasis); Rashid supra (CD).
Since the IL-12/23 signaling pathways are mediated by Jak2/Tyk2 heterodimer via phosphorylation of STAT3/4, developing Jak2 and Tyk2 inhibitors is of high interest to the scientific and medical community. See, e.g., Liang et al., J. Med. Chem. (2013) 56:4521-4536. Blockade of Jak2 activity, however, is viewed as problematic since Jak2 also regulates the erythropoietin signaling pathway, and its inhibition is associated with unwanted hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. See, e.g., Liang supra; Alabdulaali, Hematology Reviews (2009) 1:e10 56-61. Given the high degree of sequence homology between the Jak family kinase members, development of selective Tyk2 inhibitors, sparing Jak2 inhibition, presents a significant challenge. See e.g., Liang supra.
SUMMARY
Described herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof:
wherein R1, R2, R3, R4, R4b, X1, X2, X3, X4, X5, and n are as defined herein; and pharmaceutical compositions comprising same. Compounds of Formula (I) may potently and selectively inhibit Tyk2, with half maximal effective concentration (EC50) (as measured by the Tyk2 (Tyk2/Jak2 PSTAT4 T-Blast) alpha screen assay and Jak2 (PTATS UT7) alpha screen assay, described herein) of less than 4μM, and with a 10-fold to over 1000-fold selectivity for Tyk2 over Jak2. See, e.g.,Examples, Table C.
Further described are methods of treating a disease comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein the disease is inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or psoriasis.
Further described are methods of preparing compounds of Formula (I), or salts thereof. For example, a compound of Formula (I), or salt thereof, may be prepared by reacting a compound of Formula (D), or salt thereof:

with a compound of formula R1-LG3, wherein LG3 is a leaving group.
Alternatively, a compound of Formula (I), or salt thereof, may be prepared from palladium or copper catalyzed coupling of a compound of Formula (H), or salt thereof:

with a compound of Formula R2C(═0)NH2, or salt thereof, wherein LG4 is a leaving group.
Further described are compounds of the below formula:
and salts thereof, wherein n, X1, X2, X3, X4, X5, R1, R2, R3, R4a, R4b, LG2, LG4, R1a, R1bR1c, and PG1 are as defined herein.